The present invention relates to substituted cyclohexylcarboxylic acid amide compounds, to processes for their production, to pharmaceutical compositions containing these compounds and to the use of cyclohexylcarboxylic acid compounds for producing pharmaceutical compositions.
The treatment of chronic and non-chronic pain conditions has great importance in medicine. There is a worldwide need for effective methods of treating pain. The urgent need for action for patient-oriented and purposeful treatment of chronic and non-chronic pain conditions, this being taken to mean the successful and satisfactory treatment of pain for the patient, is documented in the large number of scientific papers which have recently appeared in the field of applied analgesics and fundamental research work on nociception.
Conventional μ-opioids such as morphine are very effective in the treatment of strong to very strong pain and are of great importance for the treatment of pain. However, it may be advantageous if, in addition to the μ-opioid receptor, other opioid receptors, in particular the ORL1 receptor, are affected since the pure μ-opioids also exhibit undesired side effects such as obstipation and respiratory depression, but may also lead to dependency. The opioid receptors δ, κ and ORL1 are also involved in the occurrence of pain (Opioids: Introduction, pp. 127-150, Further Opioid Receptors, 455-476 in: Analgesics—From Chemistry and Pharmacology to Clinical Application, Wiley VCH, 2002).
It is also known that influencing of serotonin and/or noradrenalin re-uptake can be beneficial to the effects and side effects of opioids (Example: Tramadol, cf. Opioids with Clinical Relevance: Tramadol, 228-230 in: Analgesics—From Chemistry and Pharmacology to Clinical Application, Wiley VCH, 2002).
The ORL1 receptor is also involved in the regulation of further physiological and pathophysiological processes. These include inter alia learning and memory formation (Manabe et al., Nature, 394, 1997, pp. 577-581), Hörvermögen [Hearing capacity] (Nishi et al., EMBO J., 16, 1997, pp. 1858-1864) and numerous further processes. In a synopsis by Calo et al. (Br. J. Pharmacol. 129, 2000-1261) there is an overview of the indications or biological procedures, in which the ORL1 receptor plays a part or could highly probably play a part. Mentioned inter alia are: analgesia, stimulation and regulation of nutrient absorption, effect on μ-agonists such as morphine, treatment of withdrawal symptoms, reduction of the addiction potential of opioids, anxiolysis, modulation of motor activity, memory disturbances, epilepsy; modulation of neurotransmitter release, in particular of glutamate, serotonin and dopamine, and therefore neurodegenerative diseases; affecting the cardiovascular system, triggering an erection, diuresis, anti-natriuresis, electrolyte balance, arterial blood pressure, water-retention diseases, intestinal motility (diarrhoea), relaxation of the respiratory tract, micturation reflex (urinary incontinence). The use of agonists and antagonists as anoretics, analgesics (also when administered with opioids) or nootropics will also be discussed.
Structurally related compounds are known from the prior art (WO 02090317) which have an affinity with the ORL1 receptor. An effect on noradrenalin and serotonin re-uptake has not previously been described for this structural class.